Mini-review: The neurobiology of treating substance use disorders with classical psychedelics

The potential of psychedelics to persistently treat substance use disorders is known since the 1960s. However, the biological mechanisms responsible for their therapeutic effects have not yet been fully elucidated. While it is known that serotonergic hallucinogens induce changes in gene expression and neuroplasticity, particularly in prefrontal regions, theories on how specifically this counteracts the alterations that occur in neuronal circuitry throughout the course of addiction are largely unknown. This narrative mini-review endeavors to synthesize well-established knowledge from addiction research with findings and theories regarding the neurobiological effects of psychedelics to give an overview of the potential mechanisms that underlie the treatment of substance use disorders with classical hallucinogenic compounds and point out gaps in the current understanding

The ego in psychedelic drug action – ego defenses, ego boundaries, and the therapeutic role of regression

The ego is one of the most central psychological constructs in psychedelic research and a key factor in psychotherapy, including psychedelic-assisted forms of psychotherapy. Despite its centrality, the ego-construct remains ambiguous in the psychedelic literature. Therefore, we here review the theoretical background of the ego-construct with focus on its psychodynamic conceptualization. We discuss major functions of the ego including ego boundaries, defenses, and synthesis, and evaluate the role of the ego in psychedelic drug action. According to the psycholytic paradigm, psychedelics are capable of inducing regressed states of the ego that are less protected by the ego’s usual defensive apparatus. In such states, core early life conflicts may emerge that have led to maladaptive ego patterns. We use the psychodynamic term character in this paper as a potential site of change and rearrangement; character being the chronic and habitual patterns the ego utilizes to adapt to the everyday challenges of life, including a preferred set of defenses. We argue that in order for psychedelic-assisted therapy to successfully induce lasting changes to the ego’s habitual patterns, it must psycholytically permeate the characterological core of the habits. The primary working principle of psycholytic therapy therefore is not the state of transient ego regression alone, but rather the regressively favored emotional integration of those early life events that have shaped the foundation, development, and/or rigidification of a person’s character – including his or her defense apparatus. Aiming for increased flexibility of habitual ego patterns, the psycholytic approach is generally compatible with other forms of psychedelic-assisted therapy, such as third wave cognitive behavioral approaches

A common molecular mechanism for cognitive deficits and craving in alcoholism

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism

Primary Transgenic Bovine Cells and Their Rejuvenated Cloned Equivalents Show Transgene-Specific Epigenetic Differences

Cell-mediated transgenesis, based on somatic cell nuclear transfer (SCNT), provides the opportunity to shape the genetic make-up of cattle. Bovine primary fetal fibroblasts, commonly used cells for SCNT, have a limited lifespan, and complex genetic modifications that require sequential transfections can be challenging time and cost-wise. To overcome these limitations, SCNT is frequently used to rejuvenate the cell lines and restore exhausted growth potential. We have designed a construct to be used in a 2-step cassette exchange experiment. Our transgene contains a puromycin resistance marker gene and an enhanced green fluorescence protein (EGFP) expression cassette, both driven by a strong mammalian promoter, and flanked by loxP sites and sequences from the bovine β-casein locus. Several transgenic cell lines were generated by random insertion into primary bovine cell lines. Two of these original cell lines were rederived by SCNT and new primary cells, with the same genetic makeup as the original donors, were established. While the original cell lines were puromycin-resistant and had a characteristic EGFP expression profile, all rejuvenated cell lines were sensitive to puromycin, and displayed varied EGFP expression, indicative of various degrees of silencing. When the methylation states of individual CpG sites within the transgene were analyzed, a striking increase in transgene-specific methylation was observed in all rederived cell lines. The results indicate that original transgenic donor cells and their rejuvenated derivatives may not be equivalent and differ in the functionality of their transgene sequences

Half a century of amyloids: past, present and future

Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-ß architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward. This journal i

Sex- and age-specific effects on the development of addiction and compulsive-like drinking in rats

Abstract Background Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. Methods Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats. Results Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). Conclusions Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments

Average methylation of the analyzed DNA sequences in rederived and original cell lines.

ab<p>values for the methylation within a specific region with these superscripts differ significantly; P<0.0005.</p>cd<p>values for the methylation within a specific region with these superscripts differ significantly; P<0.026.</p>ef<p>values for the methylation within a specific region with these superscripts differ significantly; P<0.009.</p>eg<p>the difference of the methylation values with these superscripts are just outside the significance level (P<0.052). The P-value is 0.007 with a t-test assuming equal variances.</p

DNA methylation levels of transgene and endogenous genomic DNA sequences in original and rederived cells.

<p>(a) Schematic representation of the transgene construct (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035619#pone-0035619-g001" target="_blank">Fig. 1</a> for a detailed description) depicting the location of the analyzed regions I, II, III and BCP. The black bars underneath indicate positions of CpGs within the transgene sequence. Methylation levels are shown as heatmap data with each square representing the average methylation level (expressed in proportional values with 0 = 0% methylated and 1 = 100% methylated) for a specific cleavage fragment. The numbers below the heatmap identify individual CpGs that are present on each of the analyzed cleavage fragments. The numbering itself refers to the order of the CpG sites as they appear in the DNA sequence. Alphabetic characters highlight fragments of the same mass/charge ratio which cannot be resolved by the QHTMS approach and only allows for conveying an average methylation value for these fragments. (b) Display of the methylation heatmap for two endogenous sequences in original and rederived cells. Numbers and alphabetical characters have been used as described under (a). ND: CpGs where the proportional methylation could not be determined.</p

Transgene construct and cell line isolation and rederivation scheme.

<p>(a) The transgene construct is comprised of a puromycin-resistance gene (Puro) and an EGFP gene (EGFP), each driven by an individual TK promoter (pTK) and flanked firstly by a pair of incompatible lox sites (loxP, lox2272) and secondly homologous sequence arms of the bovine beta-casein promoter (5′ β-CN) and 3′ untranslated region (3′ β-CN). (b) Primary bovine cells were transfected and cell clones isolated following antibiotic selection. Two cell clones (A and B) were chosen as source for donor cells to generate embryos using SCNT. Following transfer into recipient cows for further in vivo development, two resulting fetuses generated from cell line A (fetus A1, A2) and cell line B (fetus B1 and B2) were used to isolate a series of rejuvenated primary cell lines with the same genetics as the original cell lines A (A1-1, A1-2, A2-3, A2-4, A2-5, A2-6) and B (B1-1, B1-2, B2-1).</p